It has previously been shown that the consumption of probiotics may have beneficial effects not only on peripheral tissues but also on the central nervous system and behavior via the microbiota–gut–brain axis, raising the possibility that treatment with probiotics could be an effective therapeutic strategy for managing neurodegenerative disorders. In this study, we investigated the effects of oral administration of Bifidobacterium breve strain A1 (B. breve A1) on behavior and physiological processes in Alzheimer’s disease (AD) model mice. We found that administration of B. breve A1 to AD mice reversed the impairment of alternation behavior in a Y maze test and the reduced latency time in a passive avoidance test, indicating that it prevented cognitive dysfunction. We also demonstrated that non-viable components of the bacterium or its metabolite acetate partially ameliorated the cognitive decline observed in AD mice. Gene profiling analysis revealed that the consumption of B. breve A1 suppressed the hippocampal expressions of inflammation and immune-reactive genes that are induced by amyloid-β. Together, these findings suggest that B. breve A1 has therapeutic potential for preventing cognitive impairment in AD.

In our previous study, we reported the therapeutic potential of Bifidobacterium breve A1 in preventing cognitive impairment in a mouse model of Alzheimer’s disease and participants with mild cognitive impairment; we suggested that probiotic supplementation is an effective therapeutic strategy for managing cognitive function. Accordingly, we conducted a randomised, double-blind, placebo-controlled trial to assess whether 12-week B. breve A1 supplementation could affect the cognitive function of elderly subjects with memory complaints. We assessed cognitive function using the Japanese version of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Mini-Mental State Examination (MMSE) at baseline and after 12 weeks of probiotic supplementation. A total of 121 participants were randomised and received B. breve A1 capsules or placebo daily for 12 weeks; of these, 117 participants completed the study. At 12 weeks, neuropsychological test scores significantly increased in both groups; no significant intergroup difference was observed in terms of changes in scores from the baseline scores. However, a stratified analysis revealed a significant difference between B. breve A1 and placebo groups in terms of the subscale ‘immediate memory’ of RBANS and MMSE total score in the subjects with low RBANS total score at baseline. No significant differences in terms of blood parameters between the groups or adverse effects caused by B. breve A1 intervention were observed. The results of the present study suggest the safety of B. breve A1 supplementation and its potential in maintaining cognitive function in elderly subjects with memory complaints. However, future large-scale studies on individuals with impaired cognitive function are required to validate the present findings.

Physical exercise exerts favourable effects on brain health and quality of life of the elderly; some of these positive health effects are induced by the modulation of microbiota composition. We therefore conducted a randomised, double blind, placebo-controlled trial that assessed whether a combination of Bifidobacterium spp. supplementation and moderate resistance training improved the cognitive function and other health-related parameters in healthy elderly subjects. Over a 12-week period, 38 participants (66-78 years) underwent resistance training and were assigned to the probiotic Bifidobacterium supplementation (n=20; 1.25×10 cfu each of Bifidobacterium longum subsp. longum BB536, B. longum subsp. infantis M-63, Bifidobacterium breve M-16V and B. breve B-3) or the placebo (n=18) group. At baseline and at 12 weeks, we assessed the cognitive function, using the Japanese version of the Montreal Cognitive Assessment instrument (MoCA-J); modified flanker task scores; depression-anxiety scores; body composition; and bowel habits. At 12 weeks, the MoCA-J scores showed a significant increase in both the groups, while the flanker task scores of the probiotic group increased more significantly than those of the placebo group (0.35±0.9 vs -0.29±1.1, P=0.056). Only the probiotic group showed a significant decrease in the depression-anxiety scores (5.2±6.3 to 3.4±5.5, P=0.012) and body mass index (24.0±2.8 to 23.5±2.8 kg/m, P<0.001), with a significant increase in the defecation frequency (5.3±2.3 to 6.4±2.3 times/5 days, P=0.023) at 12 weeks. Thus, in healthy elderly subjects, combined probiotic bifidobacteria supplementation and moderate resistance training may improve the mental condition, body weight and bowel movement frequency.

Evidence linking the gut-brain axis to Alzheimer's disease (AD) is accumulating, but the characteristics of causally important microbes are poorly understood. We perform a fecal microbiome analysis in healthy subjects and those with mild cognitive impairment (MCI) and AD. We find that Faecalibacterium prausnitzii (F. prausnitzii) correlates with cognitive scores and decreases in the MCI group compared with the healthy group. Two isolated strains from the healthy group, live Fp360 and pasteurized Fp14, improve cognitive impairment in an AD mouse model. Whole-genome comparison of isolated strains reveals specific orthologs that are found only in the effective strains and are more abundant in the healthy group compared with the MCI group. Metabolome and RNA sequencing analyses of mouse brains provides mechanistic insights into the relationship between the efficacy of pasteurized Fp14, oxidative stress, and mitochondrial function. We conclude that F. prausnitzii strains with these specific orthologs are candidates for gut microbiome-based intervention in Alzheimer's-type dementia.

There is a growing interest in identifying natural food ingredients that may serve to prevent dementia such as that due to Alzheimer disease (AD). Peptides derived from food proteins have been demonstrated to have various physiological activities such as a hypotensive action. Recent findings have indicated possible associations of hypertension with AD progression, and suggest that angiotensin converting enzyme (ACE) inhibitors with potential to pass through the blood brain barrier (BBB) may reduce the risk of AD. In this study, we investigated the effect of milk peptide (CH-3) on cognitive function in AD model mice. CH-3 contains a tripeptide (methionine-lysine-proline, MKP) that has been found to have a strong ACE inhibitory effect and the potential to pass through the BBB. Adult male ddY mice were used in this study, and an animal model of AD was induced by intracerebroventricular (ICV) injection of Aβ1–42. CH-3 (250 mg/kg/day) or MKP (0.5 mg/kg/day) was orally administered every day starting 2 days before ICV injection. At 3 weeks after ICV injection, cognitive function was evaluated by the Morris water maze test. Brain samples were obtained after behavioral testing, and expression of inflammatory cytokines and NADPH oxidase subunits was measured by real-time quantitative RT-PCR. ICV injection of Aβ1–42 significantly impaired cognitive function compared with that in PBS-injected mice. Daily administration of CH-3 markedly attenuated this Aβ1-42-induced cognitive decline. Aβ1–42 injection significantly enhanced the expression of tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) and p22phox in the mouse hippocampus compared with PBS injection, and showed a tendency to increase the expression of monocyte chemoattractant protein-1 (MCP-1), p47phox and gp91phox, whereas CH-3 treatment markedly reduced Aβ1-42-induced TNF-α, MCP-1, iNOS, p47phox and gp91phox expression. Finally, administration of MKP also attenuated Aβ1-42-induced cognitive impairment with an increase in cerebral blood flow. The present study demonstrated that repeated oral administration of CH-3 to AD model mice not only improved cognitive function but also suppressed the expression of inflammatory cytokines and production of oxidative stress, and suggests its therapeutic potential for preventing cognitive impairment in AD.

The gut microbiota is involved in the pathogenesis of stress-related disorders. Probiotics can benefit the central nervous system via the microbiota–gut–brain axis, which raises the possibility that probiotics are effective in managing depression. In the present study, we examined the effects of heat-killed Lactobacillus helveticus strain MCC1848 in subchronic and mild social defeat stress (sCSDS) model mice (a widely used animal model of depression). MCC1848 supplementation significantly enhanced the interaction time in the social interaction test and sucrose preference ratio in the sucrose preference test, suggesting that MCC1848 improved anxiety- or depressive-like behaviors in sCSDS mice. The gene expression profile analysis of the nucleus accumbens, which plays an important role in stress resilience, indicated that MCC1848 ameliorated sCSDS-induced gene expression alterations in signal transduction or nervous system development. These findings suggest that MCC1848 supplementation is useful as a preventive strategy for chronic-stress-induced depression.

Objectives: We previously reported the therapeutic potential of Bifidobacterium breve A1 (B. breve A1) for preventing cognitive impairment in Alzheimer’s disease model mice, which suggested that supplementation of the probiotics could be an effective therapeutic strategy for managing cognitive function in mild cognitive impairment (MCI). Design and settings: We conducted an open-label, single-arm study to examine the effects of 24-week supplementation of B. breve A1 on elderly with MCI in Aki Orthopedics Rehabilitation Clinic in Japan. Participants: 27 participants were screened by their Mini Mental State Examination (MMSE) scores. Measurements: Cognitive function was assessed using MMSE and Digit Symbol Substitution Test (DSST) at baseline and every 8 weeks. Mental condition and quality of life for gastrointestinal symptoms were measured using the Profile of Mood States 2nd Edition (POMS2), and the Gastrointestinal Symptom Rating Scale (GSRS). Results: Of the 27 participants enrolled, 19 completed the study. MMSE scores were significantly increased during the intervention by mixed model Dunnett’s test and Wilcoxon signed-rank tests (+1.7, P < 0.01). POMS2 and GSRS scores were significantly improved during intervention when analyzed by Wilcoxon signed-rank tests. Conclusion: The present study showed that oral supplementation of B. breve A1 in participants with MCI improved cognitive function, thus suggesting the potential of B. breve A1 for improving cognitive function and maintaining quality of life of the elderly. Further randomized, double-blind placebo-controlled studies are worth conducting to examine the beneficial effect of B. breve A1.

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